The papillomaviruses are a group of small DNA viruses associated with benign proliferative lesions in a variety of higher vertebrates. A subgroup of viruses are associated with lesions which can progress to malignancy. There are currently 60 different human papillomaviruses and six different bovine papillomaviruses that have been described. The life cycle of these viruses is closely linked to the differentiation program of squamous epithelial cells which are the natural host for these viruses and, to date, no culture system has yet been developed for the successful propagation of any papillomaviruses in the laboratory. The bovine papillomavirus type 1 (BPV-l) has served as the prototype of the papillomaviruses for genetic and molecular studies. BPV-L virus readily transforms a variety of rodent cells in tissue culture, and a unique feature of the transformed cells is that the viral DNA often remains as the stable extrachromosomal plasmid within the cells. Our studies have been designed to focus on the molecular biology of the BPV-I as a model for understanding the normal host cell interaction with the idea of gaining insight into the viral and cellular factors involved in viral gene expression and carcinogenic progression. Within the viral system, the E2 gene products have served as critical factors in regulating viral gene expression. The E2 open reading frame of BPV-I encodes three distinct proteins with DNA binding properties. These proteins have both negative and positive effects on the regulation of viral gene expression. Our studies have been designed to shed understanding on this regulation in terms of the target of these sequences within the viral genome and in terms of the biochemical properties of the E2 proteins.